A Study of Therapy for Pediatric Relapsed or Refractory Acute Lymphoblastic Leukemia
A Study of Therapy for Pediatric Relapsed or Refractory Acute Lymphoblastic Leukemia
The main purpose of this study is to find out how well participants with relapsed or refractory ALL respond to treatment with an etoposide- and teniposide-based induction chemotherapy regimen and what the side effects are.
Primary Objectives:
In this study, subjects will be divided into high-risk and standard-risk subgroups according to the length of their first remission, the type of early cancer cell (T or B-cell) and the site or sites of disease relapse. The remission induction phase (the beginning phase of therapy) will consist of three blocks of therapy. Block A features daily IV low-dose etoposide in combination with cytarabine given by continuous IV, weekly vincristine, and daily dexamethasone. In block B, a combination of weekly PEG-asparaginase, vincristine, and daily dexamethasone will be given. Block C will be a combination of high-dose methotrexate, high-dose cytarabine, and teniposide.
There will be two phases of consolidation (treatment phase after induction therapy). Additional therapy will be given between the two consolidation phases. Continuation will consist of eight weekly cycles of chemotherapy. Periodic intrathecal therapy (medicine given into the spinal fluid) will be given throughout the treatment. Participants who do not achieve remission (absence of leukemia) after consolidation will be offered enrollment on St. Jude NKEHM protocol (NK cell transplant). Hematopoietic stem cell transplant (HSCT) is planned for participants with high risk disease. HSCT will be done according to current institutional practice. The duration of chemotherapy will be one year for patients with extramedullary (outside the bone marrow) relapse and two years for all others.
Exploratory objectives include:
Detailed Description of Treatment Plan:
All patients will receive the same remission induction. All high-risk patients will be offered HSCT which will be performed after a suitable donor is identified and preferably after MRD becomes negative. If they do not have a donor or they refuse HSCT, they will continue to receive chemotherapy. Standard-risk patients continue chemotherapy if MRD is negative after induction, but will be offered HSCT if MRD is >0.01% after Block C of Induction. Those who do not achieve morphological CR after induction will be treated according to the contingency plan.
Block A (14 days)
Dexamethasone 5 mg/m2/day, days 1-14
Vincristine 1.5 mg/m2 (max 2 mg), days 1 and 8
Etoposide 25 mg/m2, days 1-14
Cytarabine 25 mg/m2, days 1-14
All patients will proceed to Block B if the clinical condition permits.
CNS prophylaxis (IT MHA)
CNS-1: At the time of relapse and day 14.
CNS-2 and 3: At the time of relapse, day 8 and 14.
Leucovorin: 5 mg/m2 (5 mg max dose) PO, 24 and 30 hours after each IT MHA.
Block B (15 days)
All patients will proceed to Block B immediately after Block A if they are clinically well.
Dexamethasone 6 mg/m2, Days 1-14
Vincristine 1.5 mg/m2, days 1 and 8
PEG-Asparaginase 2500 units/m2, days 1, 8 and 15
CNS prophylaxis (IT MHA): CNS-2 or 3 only, if necessary.
Leucovorin: 5 mg/m2 (5 mg max) PO 24 and 30 hours after each IT MHA
Block C (1 day)
All patients who received Block B will proceed to Block C when WBC >1,000/microL, ANC >300/microL and platelets >50,000 microL after recovery from Block B.
Methotrexate 8 gm/m2, day 1
Cytarabine 1 g/m2 at least 24 h after ITHMA, day 1
Teniposide 165 mg/m2, day 1
CNS prophylaxis (IT MHA):
Leucovorin: 5 mg/m2 (5 mg maximum dose) PO 24 and 30 hours after each IT MHA
Consolidation I
This is a 4-week phase. It will be started if WBC >1000/microL, ANC >500/microL and platelets >50,000 /microL
Week 1: Dex day 1, 2, 3, PEG, VCR, Mito day 4
Week 2: Dex day 1, 2, 3, PEG, VCR, day 4
Week 3: Dex day 1, 2, 3, PEG, VCR, Mito day 4
Week 4: Dex day 1, 2, 3, PEG, VCR, day 4
Dexamethasone 8 mg/m2/day, day 1-3
PEG-Asparaginase 2500 units/m2 IM, day 4 each week
Vincristine 2 mg/m2 (max 2 mg), day 4 each week
Mitoxantrone 12 mg/m2, day 4 week 1 and 3
Interim Continuation
Week 1*†:
etoposide 300 mg/m2 IV, 1 dose on day 1
Cyclophosphamide 300 mg/m2 IV, 1 dose on day 1
Week 2*:
Methotrexate 40 mg/m2 IV, 1 dose on day 1
6-mercaptopurine# 75 mg/m2 PO, Days 1 to 7
Week 3*:
teniposide 150 mg/m2 IV, 1 dose on day 1
Cytarabine 300 mg/m2 IV, 1 dose on day 1
Week 4*:
Dexamethasone§ 12 mg/m2/day PO, TID Days 1 to 5
Vinblastine 6 mg/m2 IV (max 10 mg), 1 dose on day 1
Consolidation II
Week 1*†:
etoposide 300 mg/m2 IV, 1 dose on day 1
Cyclophosphamide 300 mg/m2 IV, 1 dose on day 1
Week 2*:
Methotrexate 40 mg/m2 IV, 1 dose on day 1
6-mercaptopurine# 75 mg/m2 PO, Days 1 to 7
Week 3*:
teniposide 150 mg/m2 IV, 1 dose on day 1
Cytarabine 300 mg/m2 IV, 1 dose on day 1
Week 4*:
Dexamethasone§ 12 mg/m2/day PO, TID, Days 1 to 5
Vinblastine 6 mg/m2 IV (max 10 mg), 1 dose on day 1
Continuation
Week 1*†¶:
etoposide 300 mg/m2 IV, 1 dose on day 1
Cyclophosphamide 300 mg/m2 IV, 1 dose on day 1
Week 2*:
Methotrexate 40 mg/m2 IV, 1 dose on day 1
6-mercaptopurine# 75 mg/m2 PO, QHS, Days 1 to 7
Week 3*:
teniposide 150 mg/m2 IV, 1 dose on day 1
Cytarabine 300 mg/m2 IV, 1 dose on day 1
Week 4:
Dexamethasone§ 12 mg/m2/day PO, TID, Days 1 to 5
Vincristine§ 2 mg/m2 IV(maximum 2mg), 1 dose on day 1
Week 5*‡:
etoposide 300 mg/m2 IV, 1 dose on day 1
Cyclophosphamide 300 mg/m2 IV, 1 dose on day 1
Week 6*:
Methotrexate 40 mg/m2 IV, 1 dose on day 1
6-mercaptopurine# 75 mg/m2 PO, QHS, Days 1 to 7
Week 7*:
teniposide 150 mg/m2 IV, 1 dose on day 1
Cytarabine 300 mg/m2 IV, 1 dose on day 1
Week 8*:
Dexamethasone§ 12 mg/m2/day PO, TID, Days 1 to 5
Vinblastine 6 mg/m2 IV(max 10 mg), 1 dose on day 1
Plan for Stem Cell Transplant
Patients who have positive MRD (high-risk or standard-risk) at the end of induction or all high-risk patients regardless of MRD are eligible for HSCT
All standard-risk patients will continue chemotherapy if MRD is negative (<0.01%) after induction.
Contingency Plan
Patients who do not achieve morphological CR (M1 marrow) after Induction
If CR (M1 marrow) is not achieved after Induction, patients will proceed to Consolidation I. If they do not achieve CR after Consolidation I, they will be offered enrollment on the St. Jude NKHEM protocol or offered alternative therapy. If they do not achieve CR after NKHEM, they will come off treatment.
Patients who achieve CR but have positive MRD (>0.01%) after Block C of induction: Become eligible for HSCT. Up to two more courses of chemotherapy (course 1 and 2) will be given to attempt reducing MRD. They will receive HSCT as soon as MRD becomes negative (MRD may be repeated every 2-4 weeks as indicated).
Standard-risk patients who have positive MRD (>0.01%) after Block B will proceed to Block C. Patients in this category will become candidates for HSCT, but if MRD becomes negative after Block C, the management will be discussed with Transplant Service. Chemotherapy may be administered to reduce MRD prior to HSCT. Patients will be transplanted as soon as the MRD becomes negative.
Patients (high-risk or standard-risk) who achieved CR, but have positive MRD (>0.01%) after Block C of Induction will become eligible for HSCT. Up to two more courses of chemotherapy (course 1 and 2) will be given to attempt reducing MRD. They will receive HSCT as soon as MRD becomes negative. If MRD remains positive after course 2, then, they will proceed to HSCT after discussion with Transplant Service.
Course 1
Give chemotherapy according to the plan for Consolidation I. Start it immediately regardless of CBC. BMA will be performed when WBC >1000/microL, ANC >300/microL and platelets >50,000/microL. If MRD is negative, they will receive HSCT.
Course 2
This course will be given if MRD is positive after Course 1. Patients will be offered enrollment on St. Jude NKHEM protocol.
If they are still MRD positive after Course 2, patients may receive Interim Continuation, Consolidation II, and then Continuation until MRD becomes negative or while awaiting HSCT.
Inclusion Criteria
Exclusion Criteria